There are likely to be gender differences in relapse to drug use following abstinence in cocaine-dependent individuals. In our current SCOR human laboratory study, gender differences in the response to a social stressor and cocaine cues in cocaine-dependent individuals has been demonstrated. Additionally, work from another current MUSC SCOR project has demonstrated sex differences in response to cocaine-conditioned cue and cocaine-primed reinstatement in animal models which was correlated with reduced plasma progesterone levels. Although gender differences in factors such as stress and conditioned cues that contribute to relapse in cocaine-dependent individuals have been studied independently, the interaction of stress and cues and the effect of hormonal status on response has not been directly explored. The proposed study will build on the work done during the last funding period by studying the role of hormonal status on the response to cocaine-related cues with or without stress in cocaine-dependent women and men. This project will also be important in extending an animal model of pharmacologically-induced stress (yohimbine-induced stress) to a human laboratory setting. As such, this project will use the exact same stressor as the proposed synergistic basic science project (Project 1), providing a high degree of homology and integration. This project will further the ability to directly translate findings from an animal model of relapse to an ecologically valid test of relapse in cocaine-dependent humans and explore the impact of hormonal status on response in this model. As a further integration of the research focus between SCOR projects, both this study and Project 4 will explore the relationship between impulsivity and craving. The specific aims of this project are:1. To determine the interaction of a pharmacological stressor with exposure to cocaine-related cues and the impact of ovarian hormone status on this response in women;2. To explore the relationship between impulsivity, stress, and cocaine craving in cocaine-dependent men and women;and 3. To explore the relationship between the DHEA/cortisol ratio and response to a pharmacologic stressor in control and cocaine-dependent men and women. The interaction of stress and cues has not been systematically investigated although this paradigm closely mirrors real-life situations. Animal studies suggest that gonadal hormones play a role in the subjective and reinforcing effects of stimulants, but their role in cue or stress-induced craving has not been explored. In addition, there are important sex differences in the impact of stress on cognition that appear to be related to gonadal hormones. Sex differences in the cognitive response to stress, including increased impulsivity, may be important in the relationship between stress, cocaine cues and craving.